Soluble guanylate cyclase (sGC) is an enzyme producing cyclic guanosine monophosphate (cGMP) from guanosine triphosphate (GTP), and consists of a dimer of α subunit and β subunit. The β subunit is bonded to heme, and usually has an inactive structure, where the iron coordinated in the heme and the 105th histidine residue interact with each other. Nitrogen monoxide (NO) is known as a major sGC stimulating factor in vivo, and interacts with the heme iron present in the β subunit of sGC, and dissociate the interaction of the heme iron and the histidine residue of the β subunit whereby to transfer sGC to an activated form. cGMP produced by the activated sGC subsequently activates, for example, protein kinase or ion channel, and plays various roles such as relaxation of vascular smooth muscles, suppression of platelet activation, suppression of cell growth and neurotransmission of smell. Under pathological conditions, decline of sGC activity and decomposition of sGC occur, which leads to suppression of cGMPs, contraction of vascular smooth muscle, activation of platelet or cell growth, and eventually may be a cause for hypertension, pulmonary hypertension, heart failure, endothelial dysfunction, atherosclerosis, a peripheral vascular disease, angina pectoris, thrombosis, myocardial infarction, erectile dysfunction or renal dysfunction (Non Patent Documents 1 and 2).
A nitrate agent such as nitroglycerin is widely used clinically in order to activate sGC. They supply exogenous NO whereby to cause activation of sGC, and express pharmacological actions. However, the nitrate agents are known to have a tolerance in addition to side effects, which is a serious defect of this pharmaceutical agent. Suggested is that the phenomenon of tolerance to nitrate agent is due to a mechanism which is unassociated with sGC such as decline of the activity of mitochondria aldehyde dehydrogenase that is involved in release of NO (Non Patent Document 3). Thus, a compound directly activating sGC regardless of the release of NO can avoid the tolerance. In addition, under aging or pathological conditions such as, hypertension, diabetes and hyperlipidemia, it is suggested that oxidation of heme iron and decomposition of heme increase due to oxidative stress, and NO cannot interact with heme, and sufficient activation of sGC cannot be expected (Non Patent Document 4). As another sGC stimulating agent than NO, a direct sGC stimulating agent represented by Riociguat (Patent Document 1) is known, which is dependent on heme. It is shown that although these compounds activate sGC independently from NO, these compounds cannot sufficiently exhibit sGC activation ability under the oxidation condition of heme iron (Non Patent Document 5). Accordingly, it is considered that a compound having direct sGC activation effect without dependence on the oxidation state of heme differently from NO or Riociguat, is effective for treating or preventing various diseases such as hypertension, pulmonary hypertension, heart failure, endothelial dysfunction, atherosclerosis, a peripheral vascular disease, angina pectoris, thrombosis, myocardial infarction, erectile dysfunction and renal dysfunction.
As the compound having direct sGC activation effect without dependence on the oxidation state of heme, disclosed are Cinaciguat and related derivatives in Patent Document 2, pyrazole and triazole derivatives in Patent Document 3, 2,6-disubstituted pyridine derivatives in Patent Document 4, and heterocycle derivatives in Patent Document 5.